COVID19 coagulopathy in Caucasian patients Fogarty, Helen; Townsend, Liam; Ni Cheallaigh, Cliona ...
British journal of haematology,
June 2020, Letnik:
189, Številka:
6
Journal Article
Recenzirano
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Summary
Although the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung‐centric coagulopathy may play an important role. Elevated D‐dimer ...levels which correlated inversely with overall survival were recently reported in Chinese cohort studies. Critically however, ethnicity has major effects on thrombotic risk, with a 3–4‐fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African‐Americans. In this study, we investigated COVID19 coagulopathy in Caucasian patients. Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity. Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC). In rare COVID19 cases where DIC does develop, it tends to be restricted to late‐stage disease. Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary‐specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC. Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality.
Novel coronavirus disease 2019 (COVID-19) infection occurring during pregnancy is associated with an increased risk of preterm delivery. This case report describes successful treatment of preterm ...labor during acute COVID-19 infection. Standard treatment for preterm labor may allow patients with acute COVID-19 infection to recover without the need for preterm delivery. KEY POINTS: · Acute COVID-19 infection is associated with a high rate of preterm delivery.. · Standard treatment for preterm labor such as intravenous magnesium sulfate, antepartum steroid therapy and antibiotic prophylaxis for group B streptococcus infection were effective in this patient.. · In the absence of maternal or fetal compromise, acute COVID-19 infection is not an indication for early elective delivery..
We have recently described a novel guanidinium-based compound, VP79s, which induces cytotoxicity in various cancer cell lines. Here, we aim to investigate the activity of VP79s and associated ...mechanisms of action in multiple myeloma (MM) cells in vitro and ex vivo.
The effects of VP79s on cell viability and induction of apoptosis was examined in a panel of drug-sensitive and drug-resistant MM cell lines, as well as ex vivo patient samples and normal donor lymphocytes and platelets. Cell signaling pathways associated with the biological effects of VP79s were analysed by immunoblotting and flow cytometry. Gene expression changes were assessed by quantitative real-time PCR analysis.
VP79s was found to rapidly inhibit both constitutively active and IL-6-induced STAT3 signaling with concurrent downregulation of the IL-6 receptors, CD130 and CD126. VP79s induced a rapid and dose-dependent downregulation of anti-apoptotic Bcl-2 family member, myeloid cell leukaemia-1 (MCL-1). VP79s enhanced bortezomib induced cell death and was also found to overcome bone marrow stromal cell induced drug resistance. VP79s exhibited activity in ex vivo patient samples at concentrations which had no effect on peripheral blood mononuclear cells, lymphocytes and platelets isolated from healthy donors.
As VP79s resulted in rapid inhibition of the key IL-6/STAT3 signaling pathway and downregulation of MCL-1 expression with subsequent selective anti-myeloma activity, VP79s may be a potential therapeutic agent with a novel mechanism of action in MM cells.
•IL-6/JAK/STAT3 cell signaling pathway is a promising target in multiple myeloma.•VP79s rapidly downregulates IL-6 receptor expression and STAT3 activation.•VP79s inhibits the expression of STAT3 target genes, including MCL1.•VP79s selectively induces apoptosis in myeloma cell lines and patient samples.•VP79s enhances bortezomib activity and inhibits induced drug resistance.
Allogeneic hematopoietic cell transplantation is widely used to treat adults with high-risk acute lymphoblastic leukemia. The aim of this study was to analyze whether the results changed over time ...and to identify prognostic factors. Adult patients treated between 1993 and 2012 with myeloablative allogeneic hematopoietic cell transplantation from HLA matched sibling (n=2681) or unrelated (n=2178) donors in first complete remission were included. For transplantations from sibling donors performed between 2008 and 2012, 2-year probabilities of overall survival were: 76% (18-25 years old), 69% (26-35 and 36-45 years old) and 60% (46-55 years old). Among recipients of transplantations from unrelated donors, the respective survival rates were 66%, 70%, 61%, and 62%. In comparison with the 1993-2007 period, significant improvements were observed for all age groups except for the 26-35-year old patients. In a multivariate model, transplantations performed between 2008 and 2012, when compared to 1993-2007, were associated with significantly reduced risks of non-relapse mortality (Hazard Ratio 0.77, P=0.00006), relapse (Hazard Ratio 0.85, P=0.007), treatment failure (Hazard Ratio 0.81, P<0.00001), and overall mortality (Hazard Ratio 0.79, P<0.00001). In the analysis restricted to transplantations performed between 2008 and 2012, the use of total body irradiation-based conditioning was associated with reduced risk of relapse (Hazard Ratio 0.48, P=0.004) and treatment failure (Hazard Ratio 0.63, P=0.02). We conclude that results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia improved significantly over time. Total body irradiation should be considered as the preferable type of myeloablative conditioning.
Melphalan at a dose of 200 mg/m(2) is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m(2) is often used in clinical ...practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m(2) and melphalan 140 mg/m(2) are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m(2) (n=245) and melphalan 200 mg/m(2) (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m(2) in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m(2)versus melphalan 140 mg/m(2): 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m(2) for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m(2) and melphalan 140 mg/m(2) patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m(2) or melphalan 140 mg/m(2) for key transplant outcomes (NCT01362972).
We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal ...nocturnal hemoglobinuria (PNH).
We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed.
Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.
Eculizumab is an effective therapy for PNH.
Invariant natural killer T (iNKT) cells are cytotoxic T cells that respond to glycolipid antigens presented by CD1d. Therapeutic activation of iNKT cells with α-galactosylceramide (α-GalCer) can ...prevent and reverse tumor growth in mice and clinical trials involving α-GalCer-stimulated iNKT cells are ongoing in humans. B cells express CD1d, however, we show that CD1d expression is reduced on B cells from patients with chronic lymphocytic leukemia (CLL). B cells from CLL patients pulsed with α-GalCer failed to stimulate cytolytic degranulation by iNKT cell lines, but could present the more potent glycolipid analogue, 7DW8-5. Retinoic acid receptor-α (RAR-α) agonists induced CD1d expression by CLL B cells, restoring their ability to present α-GalCer to CD8α+ iNKT cells, resulting in cytolytic degranulation. Thus, RAR-α agonists can augment the anti-tumor activities of iNKT cells against CLL cells in vitro. Their inclusion in iNKT cell-based therapies may benefit patients with CLL.
•CD1d expression is reduced on B cells from CLL patients.•CLL B cells have reduced capacity to present glycolipid antigens to iNKT cells.•Retinoic acid induces CD1d expression by CLL B cells.•Retinoic acid primes CLL B cells for killing by CD8α+ iNKT cells•Including retinoic acid in iNKT cell-based therapies may benefit patients with CLL.
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